Methods and Devices for Reducing Tissue Damage After Ischemic Injury

Abstract

Methods and devices are provided for the delivery of therapeutic agents which reduce myocardial tissue damage due to ischemia and anti-restenotic agents which inhibit restenosis following a cardiac procedure such as stent implantation. The anti-ischemia agents are delivered to the myocardial tissue over an administration period sufficient to achieve reduction in ischemic or reperfusion injury of the myocardial tissue. The anti-restenotic agents are delivered over an administration period sufficient to reduce the re-narrowing of a blood vessel following a cardiac procedure such as implantation of a device. Preferred anti-restenotic drugs are those that do not reduce the beneficial effects provided by the anti-ischemic drug, such as drugs that do not act on the mammalian target of rapamycin (mTOR).

1 . A method for reducing tissue damage following ischemic injury in a patient, the method comprising: 
 administering to the patient an anti-ischemic agent which reduces tissue damage due to ischemia and one or more anti-restenotic agent that reduces or prevents restenosis, wherein the anti-ischemic agent and the one or more anti-restenotic agent are administered locally to or near the site of ischemic injury, and wherein the anti-restenotic agent does not reduce the beneficial effects provided by the anti-ischemic agent.    
     
     
         2 . The method of  claim 1 , wherein at least one of the anti-ischemic agent and anti-restenotic agent are administered in a medical device implanted at or near the site of ischemic injury.  
     
     
         3 . The method of  claim 2 , wherein the device is selected from the group consisting of stents, polymeric delivery devices, polymeric particles and polymeric coatings.  
     
     
         4 . The method of  claim 3 , wherein the at least one of anti-ischemic agent and one or more anti-restenotic agent is administered into a blood vessel.  
     
     
         5 . The method of  claim 4 , wherein the at least one of anti-ischemic agent is administered for periods of time sufficient to reduce ischemic injury.  
     
     
         6 . The method of  claim 4 , wherein the anti-restenotic drug is delivered primarily from a mural side of the medical device, and wherein the anti-ischemic agent is delivered primarily from a luminal side of the medical device.  
     
     
         7 . The method of  claim 1 , wherein the anti-restenotic agent and anti-ischemic agent are delivered from an implanted biodegradable polymer.  
     
     
         8 . The method of  claim 2 , wherein the medical device is a stent.  
     
     
         9 . The method of  claim 1 , wherein the anti-ischemic agent is insulin.  
     
     
         10 . The method of  claim 1 , wherein the anti-restenotic agent is selected from the group of compounds consisting of antineoplastics, antimitotics, antiangiogenics, angiogenic factors, anti-thrombotics, antiproliferatives, and anti-inflammatories.  
     
     
         11 . The method of  claim 1  wherein the anti-restenotic agent is pimecrolimus, sirolimus or paclitaxel.  
     
     
         12 . The method of  claim 1 , wherein the anti-ischemic and anti-restenotic agent are delivered from a polymer.  
     
     
         13 . The method of  claim 12 , wherein the polymer is in the form of polymeric coatings or particles located at or near an occlusion site.  
     
     
         14 . The method of  claim 12 , wherein the anti-ischemic agent, anti-restenotic agent and a biocompatible polymer matrix are deposited within openings in an implantable medical device for local delivery to an occlusion site.  
     
     
         15 . The method of  claim 12 , wherein the anti-ischemic agent, anti-restenotic agent and a biocompatible polymer are deposited within openings in an implantable medical device and wherein a barrier region is provided which substantially prevents delivery of the anti-ischemic agent to the artery wall.  
     
     
         16 . The method of  claim 14 , wherein the anti-ischemic agent is delivered over a period of about 1 to 72 hours.  
     
     
         17 . The method of  claim 16 , wherein the anti-restenotic agent is delivered over a period of about 30 days or longer.  
     
     
         18 . The method of  claim 17 , wherein the anti-ischemic agent and the anti-restenotic agent are delivered at different rates.  
     
     
         19 . An implantable stent for reducing tissue damage following ischemic injury in a patient, comprising: 
 an expandable stent structure:    an anti-ischemic agent affixed to the stent structure, wherein the anti-ischemic agent reduces tissue damage due to ischemia; and    one or more anti-restenotic agent that reduces or prevents restenosis wherein the anti-restenotic agent does not reduce the beneficial effects provided by the anti-ischemic agent.    
     
     
         20 . The stent of  claim 19 , wherein the anti-ischemic agent and anti-restenotic agent are released for at least one hour.  
     
     
         21 . The stent of  claim 19 , wherein the anti-ischemic agent is released for about 10 to about 48 hours.  
     
     
         22 . The stent of  claim 19 , wherein the anti-ischemic agent is insulin and the therapeutic dosage is about 5 to about 800 micrograms.  
     
     
         23 . The stent of  claim 22 , wherein the insulin is affixed to the stent by depositing in holes in the stent.  
     
     
         24 . The stent of  claim 19 , wherein the stent further comprises one or more drug sensitizers.  
     
     
         25 . The stent of  claim 24 , wherein the drug sensitizer is an insulin sensitizer.  
     
     
         26 . The stent of  claim 25 , wherein the insulin sensitizer is selected from the group consisting of biguanides, thiazolidinediones, and glitazars.  
     
     
         27 . The stent of  claim 23 , wherein the anti-restenotic agent is affixed to the stent by depositing in holes in the stent.  
     
     
         28 . The stent of  claim 19 , wherein the anti-restenotic agent and anti-ischemic agent are delivered from an implanted biodegradable polymer.  
     
     
         29 . The method of  claim 19 , wherein the anti-ischemic agent is delivered over a period of about 1 to 72 hours.  
     
     
         30 . The method of  claim 29 , wherein the anti-restenotic agent is delivered over a period of about 30 days or longer.